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The Journal of Immunology, 2004, 173: 6619-6626.
Copyright © 2004 by The American Association of Immunologists

Cellular FLIP (Long Isoform) Overexpression in T Cells Drives Th2 Effector Responses and Promotes Immunoregulation in Experimental Autoimmune Encephalomyelitis1

Vivian Tseveleki*, Jan Bauer{ddagger}, Era Taoufik*, Chengmai Ruan*, Leondios Leondiadis{dagger}, Sylva Haralambous*, Hans Lassmann{ddagger} and Lesley Probert2,*

* Laboratory of Molecular Genetics, Hellenic Pasteur Institute, and {dagger} Laboratory of Mass Spectrometry and Dioxin Analysis, National Center for Scientific Research Demokritos, Athens, Greece; and {ddagger} Division of Neuroimmunology, Brain Research Institute, Vienna, Austria

Cellular FLIP (c-FLIP) is an endogenous inhibitor of death receptor-induced apoptosis through the caspase 8 pathway. It is an NF-{kappa}B-inducible protein thought to promote the survival of T cells upon activation, and its down-regulation has been implicated in activation-induced cell death. We have generated transgenic mice overexpressing human c-FLIP long form (c-FLIPL) specifically in T cells using the CD2 promoter (TgFLIPL). TgFLIPL mice exhibit increased IgG1 production upon stimulation by a T cell-dependent Ag and a markedly enhanced contact hypersensitivity response to allergen. In addition to showing augmented Th2-type responses, TgFLIPL mice are resistant to the development of myelin oligodendrocyte glycoprotein 35–55 peptide-induced experimental autoimmune encephalomyelitis, a Th1-driven autoimmune disease. In vitro analyses revealed that T cells of TgFLIPL mice proliferate normally, but produce higher levels of IL-2 and show preferential maturation of Th2 cytokine-producing cells in response to antigenic stimulation. After adoptive transfer, these (Th2) cells protected wild-type recipient mice from experimental autoimmune encephalomyelitis induction. Our results show that the constitutive overexpression of c-FLIPL in T cells is sufficient to drive Th2 polarization of effector T cell responses and indicate that it might function as a key regulator of Th cell differentiation.




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